1. Field of the Invention
The present invention relates to a gel composition that can be implanted into a desired location and which can provide controlled release of a beneficial agent. The present invention also relates to methods of controlling release of a beneficial agent from a composition.
2. Description of the Related Art
Biodegradable polymers have been used for many years in medical applications. Illustrative devices composed of the biodegradable polymers include sutures, surgical clips, staples, implants, and sustained release drug delivery systems. The majority of these biodegradable polymers have been based upon glycolide, lactide, caprolactone, and copolymers thereof.
The biodegradable polymers can be thermoplastic materials which means that they can be heated and formed into various shapes such as fibers, clips, staples, pins, films, etc. Alternatively, they can be thermosetting materials formed by crosslinking reactions which lead to high-molecular-weight materials that do not melt or form flowable liquids at high temperatures.
Although thermoplastic and thermosetting biodegradable polymers have many useful biomedical applications, there are several important limitations to their use in the bodies of various animals including humans, animals, birds, fish, and reptiles. Because these polymers generally are solids, all instances involving their use have required initially forming the polymeric structures outside the body, followed by insertion of the solid structure into the body. For example, sutures, clips, and staples are all formed from thermoplastic biodegradable polymers prior to use. When inserted into the body, they retain their original shape. While this characteristic is essential for some uses, it is not preferred where it is desired that the material be molded or flow to fill voids or cavities where it may be most needed.
Drug delivery systems using thermoplastic or thermosetting biodegradable polymers also often are or have to be formed outside the body. In such instances, the drug is incorporated into the polymer and the mixture is shaped into a certain form such as cylinder, disc, or fiber for implantation. With such solid implants, the drug delivery system has to be inserted into the body through an incision. These incisions are sometimes larger than desired by the medical profession and occasionally lead to a reluctance of the patient to accept such an implant or drug delivery system. Nonetheless, both biodegradable and non-biodegradable implantable drug delivery systems have been widely used successfully.
One reservoir device having a rate-controlling membrane and zero-order release of an agent that is particularly designed for intraoral implantation is described in U.S. Pat. No. 5,085,866. The device is prepared from a core that is sprayed with a solution having a polymer and a solvent that is composed of a rapidly evaporating, low boiling point first solvent and a slowly evaporating, high boiling point second solvent.
Other illustrative osmotic delivery systems include those disclosed in U.S. Pat. Nos. 3,797,492, 3,987,790, 4,008,719, 4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,151,093, 5,234,692, 5,234,693, 5,279,608, and 5,336,057. Pulsatile delivery devices are also known which deliver a beneficial agent in a pulsatile manner as disclosed in U.S. Pat. Nos. 5,209,746, 5,308,348, and 5,456,679.
One way to avoid the incision needed to implant drug delivery systems is to inject them as small particles, microspheres, or microcapsules. For example, U.S. Pat. No. 5,019,400 describes the preparation of controlled release microspheres via a very low temperature casting process. These materials may or may not contain a drug which can be released into the body. Although these materials can be injected into the body with a syringe, they do not always satisfy the demand for a biodegradable implant. Because they are particulate in nature, they do not form a continuous film or solid implant with the structural integrity needed for certain prostheses. When inserted into certain body cavities such as a mouth, a periodontal pocket, the eye, or the vagina where there is considerable fluid flow, these small particles, microspheres, or microcapsules are poorly retained because of their small size and discontinuous nature. Further, the particles tend to aggregate and thus their behavior is hard to predict. In addition, microspheres or microcapsules prepared from these polymers and containing drugs for release into the body are sometimes difficult to produce on a large scale, and their storage and injection characteristics present problems. Furthermore, one other major limitation of the microcapsule or small-particle system is their lack of reversibility without extensive surgical intervention. That is, if there are complications after they have been injected, it is considerably more difficult to remove them from the body than with solid implants. A still further limitation on microparticles or microcapsulation is the difficulty in encapsulating protein and DNA-based drugs without degradation caused by denaturing solvents and temperature extremes used during processing.
The art has developed various drug delivery systems in response to the aforementioned challenges. For instance, U.S. Pat. No. 4,938,763 and its divisional U.S. Pat. No. 5,278,201 relate to a biodegradable polymer for use in providing syringeable, in-situ forming, solid biodegradable implants for animals. In one embodiment, a thermoplastic system is used wherein a non-reactive polymer is dissolved in a water soluble biocompatible solvent to form a liquid which is placed in the animal wherein the solvent dissipates to produce the solid implant. Alternatively, a thermosetting system is used wherein effective amounts of a liquid acrylic ester-terminated, biodegradable prepolymer and a curing agent are formed and the liquid mixture is placed within the animal wherein the prepolymer cures to form the solid implant. It is stated that the systems provide a syringeable, solid biodegradable delivery system by the addition of an effective level of a biologically active agent to the liquid before the injection into the animal.
U.S. Pat. No. 5,599,552 describes thermoplastic and thermoset polymer compositions that utilize solvents which are miscible to dispersible in water, such as N-methyl-2-pyrrolidone, resulting in polymer solutions capable of quickly absorbing water from surrounding tissue. The polarity of the solvents is described as being effective to provide about at least 10% solubility in water. The polymer matrix systems are described as forming a porous core surrounded by a porous skin.
U.S. Pat. No. 5,242,910 describes a sustained release composition containing drugs for treating periodontal disease. The composition comprises copolymers of lactide and glycolide, triacetin (as a solvent/plasticizer) and an agent providing relief of oral cavity diseases. The composition can take the form of a gel and can be inserted into a periodontal cavity via a syringe using either a needle or a catheter. As additional optional components, the composition can contain surfactants, flavoring agents, viscosity controlling agents, complexing agents, antioxidants, other polymers, gums, waxes/oils, and coloring agents. One illustrative viscosity controlling agent set forth in one of the examples is polyethylene glycol 400.
U.S. Pat. No. 5,620,700 describes a polymer-drug matrix, optionally including plasticizers in an amount up to about 30 wt %, for local application of drug in the peridontal cavity. Among the plasticizers listed are, inter alia, triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, diethyl phthalate, diethyl tartrate, ethyl lactate, triacetin and diacetin. The polymer matrix is non-flowable prior to administration and is heated to become flowable so that it may be dispensed into the peridontal cavity where it solidifies. While the patent discusses possible systemic applications by delivery via the ocular sacs of the eye or intravaginal delivery, it does not address the issue of burst of drug or methods of controlling burst.
U.S. Pat. No. 3,923,939 describes a method of reducing initial burst of an active agent from a delivery device by removing, prior to implantation, active agent from the exterior surface of the delivery device and through a layer of at least 5% of the overall body thickness extending from the exterior surface of the device.
U.S. Pat. No. 5,556,905 describes degradable thermoplastic compositions which are modified by plasticizers consisting of various partial esters of citric acid.
Prior art polymer compositions for injectable implants have used solvent/plasticizers that are very or relatively soluble in aqueous body fluids to promote rapid solidification of the polymer at the implant site and promote diffusion of drug from the implant. However, it has now been observed that a serious problem associated with prior art polymeric implants utilizing water soluble polymer solvents is the rapid migration of water into the polymer composition when the implant is placed in the body and exposed to aqueous body fluids. That characteristic often results in uncontrolled release of beneficial agent that is manifested by an initial, rapid release of beneficial agent from the polymer composition, corresponding to a xe2x80x9cburstxe2x80x9d of beneficial agent being released from the implant. The burst often results in a substantial portion of the beneficial agent, if not all, being released in a very short time, e.g., hours or 1-2 days. Such an effect can be unacceptable, particularly in those circumstances where sustained delivery is desired, i.e., delivery of beneficial agent over a period of a week or a month or more, or where there is a narrow therapeutic window and release of excess beneficial agent can result in adverse consequences to the subject being treated, or where it is necessary to mimic the naturally-occurring daily profile of beneficial agents, such as hormones and the like, in the body of the subject being treated.
In an attempt to control burst and modulate and stabilize the delivery of the beneficial agent the prior art has coated particles of beneficial agent to retard release into an aqueous environment and extend release of the beneficial agent over time. Alternatively, various stabilizing or release modulating agents, such as metal salts as described in U.S. Pat. Nos. 5,656,297; 5,654,010; 4,985,404 and 4,853,218 have been used. Notwithstanding some success, those methods have not been entirely satisfactory for the large number of beneficial agents that would be effectively delivered by implants, since in many instances the modulation and stabilization effect is the result of the formation of a complex of the metal ion with the beneficial agent. When such complexes do not form, the stabilization/modulation effect may not be adequate to prevent undesirable xe2x80x9cburstxe2x80x9d of the beneficial agent upon its introduction into the implant site.
Additionally, with conventional low viscosity, solvent-based depot compositions comprised of a polymer dissolved in a solvent, another problem which often exists is that the composition solidifies slowly after injection as solvent diffuses from the depot and water migrates into the depot. Since these compositions are relatively non-viscous in order to be injected, a large percentage of drug may be rapidly released as the system forms by diffusion of the solvent, particularly when the beneficial agent is soluble in the solvent and the solvent rapidly disperses into body fluids. Rapid solvent release contributes to the xe2x80x9cburstxe2x80x9d effect along with depot hardening due to water uptake. In this respect, it is typical for conventional solvent-based compositions to have a drug burst wherein 30-75% of the drug contained in the composition is released within one day of the initial injection.
The rapid water uptake into the polymer implant and solvent dispersion into body fluids exhibited by prior art devices often results in implants having pore structures that are non-homogeneous in size and shape. Typically, the surface pores take on a finger-like pore structure extending for as much as ⅓ of a millimeter or more from the implant surface into the implant, and such finger-like pores are open at the surface of the implant to the environment of use. The internal pores tend to be smaller and less accessible to the fluids present in the environment of use. Accordingly, when such devices are implanted, the finger-like pores allow very rapid uptake of aqueous body fluids into the interior of the implant with consequent immediate and rapid dissolution of significant quantities of beneficial agent and unimpeded diffusion of beneficial agent into the environment of use, producing the burst effect discussed above.
Furthermore, rapid water uptake can result in premature polymer precipitation such that a hardened implant or one with a hardened skin is produced. The inner pores and much of the interior of the polymer containing beneficial agent are shut off from contact with the body fluids and a significant reduction in the release of beneficial agent can result over a not insignificant period of time (xe2x80x9clag timexe2x80x9d). That lag time is undesirable from the standpoint of presenting a controlled, sustained release of beneficial agent to the subject being treated. What one observes, then, is a burst of beneficial agent being released in a short time period immediately after implantation, a lag time in which no or very little beneficial agent is being released, and subsequently continued delivery of beneficial agent (assuming beneficial agent remains after the burst) until the supply of beneficial agent is exhausted.
The present invention provides a method and an implantable system for systemic and local delivery of a beneficial agent to a subject. The method and system provide controlled release of beneficial agent to the subject being treated and limit the initial burst of beneficial agent from the implant system. Additionally, the invention provides a method of preparing implant systems having restricted initial burst of beneficial agent.
In one aspect, the invention comprises a method of administering, locally or systemically, a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dispersed or dissolved substantially throughout a viscous gel, the system releasing 20% or less by weight of the beneficial agent present in the viscous gel within the first 24 hours after implantation in the subject. Preferably, 10% or less by weight of the beneficial agent will be released within the first 24 hours after implantation.
In another aspect, the invention comprises a method of systemically administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dispersed or dissolved substantially throughout a viscous gel, the system having a burst index of 8 or less.
In still another aspect, the invention comprises a method of systemically administering a beneficial agent to a subject in a controlled manner approximating zero order release by implanting a gel composition comprising a biocompatible polymer, a biocompatible solvent having a solubility in water of less than 7% and forming a viscous gel with the polymer, and a beneficial agent, wherein the loading of the beneficial agent in the interior of the polymer gel is above that required to saturate the beneficial agent in water.
In still another aspect, the invention comprises an implantable, biodegradable composition for the systemic delivery of a beneficial agent to a subject wherein the composition comprises a polymer; an amount of a solvent to form a viscous gel with the polymer, and a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a single solvent or a mixture of solvents with at least one solvent having a miscibility in water of less than 7% by weight and the amount of solvent constituting 40% or more by weight of the gel vehicle.
In a further aspect, the present invention comprises an implantable, biodegradable composition for the sustained delivery of a beneficial agent to a subject wherein the composition comprises a polymer; an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a mixture of solvents with at least one solvent in the mixture having a miscibility in water of less than 7% by weight. Preferably, the miscibility in water of the solvent mixture is 20% or less by weight, and more preferably 10% or less by weight.
In yet another aspect, the invention comprises an implantable, biodegradable composition for delivery of a beneficial agent to a subject wherein the composition comprises a polymer; an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a single solvent or a mixture of solvents with at least one solvent having a miscibility in water of less than 7% by weight selected from lower alkyl and aralkyl esters of benzoic acid.
In another aspect the present invention provides an implantable gel composition for systemic delivery of a beneficial agent to a subject comprising:
A) a biocompatible polymer;
B) a biocompatible solvent, having miscibility in water of less than 7% by weight and capable of dissolving the polymer and forming a viscous gel, said solvent being selected from the group comprising compounds having the following structural formula: 
and 
wherein R1 is lower alkyl, aryl or aralkyl and R2 is aralkyl or lower alkyl; and R1 and R2 may be the same or different; with the proviso that when R1 and R2 are each lower alkyl, the number of total carbon atoms represented by R1 and R2 combined is 4 or more;
C) a beneficial agent; and, optionally, one or more of the following:
D) an emulsifying agent;
E) a pore former;
F) a solubility modulator of the beneficial agent; and
G) an osmotic agent.
In another aspect the present invention provides an implantable gel composition comprising:
A) a biocompatible polymer;
B) a biocompatible solvent having miscibility in water of less than 7% by weight and capable of dissolving the polymer and forming a viscous gel, said solvent being selected from the group comprising compounds having the following structural formula: 
wherein R1 and R2 are as defined above.
In a further aspect, the present invention provides a method of restricting uptake of water by a gel composition which comprises forming the gel composition from a polymer and a solvent that forms a viscous gel with the polymer, the solvent having a miscibility in water of less than 7% by weight. Preferably, the solvent will have a miscibility in water of 6% or less by weight, and more preferably 5% or less by weight.
In another aspect, the present invention provides a method of preparing an injectable gel composition comprising:
A) mixing a biocompatible polymer and a solvent having a miscibility in water of 7% or less selected from lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;
B) dispersing or dissolving a beneficial agent, optionally associated with a solubility modulator of the beneficial agent, in an emulsifying agent to form a beneficial agent containing emulsifying agent; and
C) mixing the beneficial agent containing emulsifying agent with the viscous gel, said beneficial agent containing emulsifying agent forming a dispersed droplet phase in the viscous gel, and optionally,
D) mixing one or more of a pore former and an osmotic agent with said viscous gel.
In another aspect, the present invention provides a method of preparing an implantable gel composition comprising:
A) mixing a biocompatible polymer and a solvent having a miscibility in water of 7% or less selected from lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;
B) dispersing or dissolving a beneficial agent, optionally associated with a solubility modulator of the beneficial agent, in the viscous gel; and;
C) optionally mixing one or more of the following: an emulsifying agent, a pore former, a solubility modulator of the beneficial agent and an osmotic agent, with the beneficial agent containing gel.
In yet another aspect, the invention provides a gel composition comprising:
A) a biocompatible polymer;
B) a biocompatible solvent having a miscibility in water of less than 7% by weight;
C) a beneficial agent selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof, and optionally, one or more of the following:
D) an emulsifying agent;
E) a pore former;
F) a solubility modulator of the beneficial agent; and
G) an osmotic agent;
wherein the composition has a burst index of less than 8.
In still another aspect, the invention comprises a kit for administration of a beneficial agent to a subject comprising:
A) a biocompatible polymer;
B) a solvent having a miscibility in water of 7% or less by weight that is suitable for dissolving the polymer and forming a viscous gel;
C) a beneficial agent; and optionally, one or more of the following:
D) an emulsifying agent;
E) a pore former;
F) a solubility modulator of the beneficial agent, optionally associated with the beneficial agent; and
G) an osmotic agent;
wherein at least the beneficial agent, optionally associated with the solubility modulator, is maintained separated from the solvent until the time of administration of the beneficial agent to a subject.
In still another aspect, the invention comprises an implantable composition for the systemic delivery of a beneficial agent comprising a poly(lactide-co-glycolide) copolymer; an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and a beneficial agent selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof, said composition having a burst index of 8 or less.
In another aspect, the invention comprises an implantable composition for the sustained delivery of a beneficial agent comprising a poly(lactide-co-glycolide) copolymer; an effective plasticizing amount of a solvent selected from lower alkyl and aralkyl esters of benzoic acid to form a viscous gel with the polymer; and a beneficial agent.
In a further aspect, the invention comprises an implantable composition comprising a viscous gel and a beneficial agent dispersed or dissolved therein, wherein the viscous gel maintains a glass transition temperature of less than 37xc2x0 C. for at least the first 24 hours after implantation.
In yet another aspect, the invention comprises a method of administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dissolved or dispersed substantially throughout a viscous gel formed of a biocompatible polymer and a solvent having a solubility in water of 7% or less, and a solubility modulator of the beneficial agent, the system having a burst index of 8 or less.
In a further aspect, the invention comprises an implantable system comprising a beneficial agent dissolved or dispersed substantially throughout a viscous gel formed of a biocompatible polymer and a solvent having a solubility in water of 7% or less, and a solubility modulator of the beneficial agent, the system having a burst index of 8 or less.